Fish and Shellfish Immunology 130 (2022) 294–308

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Fish and Shellfish Immunology

journal homepage: www.elsevier.com/locate/fsi

Bioactive immunostimulants as health-promoting feed additives in

aquaculture: A review
Seerengaraj Vijayaram a, b, Yun-Zhang Sun a, c, **, Antonio Zuorro d, Hamed Ghafarifarsani e,
Hien Van Doan f, g, *, Seyed Hossein Hoseinifar h
a
Xiamen Key Laboratory for Feed Quality Testing and Safety Evaluation, Fisheries College, Jimei University, Xiamen, China
b
Department of Environmental Studies, School of Energy Environment and Natural Resources, Madurai Kamaraj University, Madurai, India
c
The Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture, Fisheries College, Jimei University, Xiamen, China
d
Department of Chemical Engineering, Materials and Environment, Sapienza University, Via Eudossiana 18, 00184, Rome, Italy
e
Department of Fisheries, Faculty of Natural Resources, Urmia University, Urmia, Iran
f
Department of Animal and Aquatic Sciences, Faculty of Agriculture, Chiang Mai University, Chiang Mai, Thailand
g
Science and Technology Research Institute, Chiang Mai University, Suthep, Muang, Chiang Mai, Thailand
h
Department of Fisheries, Faculty of Fisheries and Environmental Sciences, Gorgan University of Agricultural Sciences and Natural Resources, Gorgan, Iran

A R T I C L E I N F O A B S T R A C T

Keywords: Bioactive immunostimulants could be derived from different sources like plants, animals, microbes, algae, yeast,
Bioactive immunostimulants etc. Bioactive immunostimulants are the most significant role to enhance aquatic production, as well as the cost
Immune system of this method, which is effective, non-toxic, and environment-friendly. These immunostimulants are supportive
Disease resistance
to increase the immune system, growth, antioxidant, anti-inflammatory, and disease resistance of aquatic ani­
Feed additives
Aquaculture
mals’ health and also improve aquatic animal feed. Diseases are mainly targeted to the immune system of aquatic
organisms in such a way that different processes of bioactive immunostimulants progress are considered
imperative techniques for the development of aquaculture production. Communicable infections are the main
problem for aquaculture, while the mortality and morbidity connected with some outbreaks significantly limit
the productivity of some sectors. Aquaculture is considered the mainly developing food production sector
globally. Protein insists is an important issue in human nutrition. Aquaculture has been an exercise for thousands
of years, and it has now surpassed capture fisheries as the most vital source of seafood in the world. Limited study
reports are available to focal point on bioactive immunostimulants in aquaculture applications. This review
report provides information on the nutritional administration of bioactive immunostimulants, their types,
functions, and beneficial impacts on aquatic animals’ health as well as for the feed quality development in the
aquaculture industry. The scope of this review combined to afford various kinds of natural derived bioactive
molecules utilization and their beneficial effects in aquaculture applications.

1. Introduction immunostimulants namely FOS, butyric acid, propionic acid, poly­

Bioactive immunostimulants have been utilized to improve aquatic
animal health, a broad spectrum of bioactive active molecules are used
to enhance aquatic animals’ health in many ways such as antimicrobial,
antioxidant, immunostimulant, growth-promoting, and anti-
inflammatory properties as well as bioactive molecules applied in
aquatic feed is the novel technique, this bioactive immunostimulant
approach reliable and reproducing methods to enhance the feed quality
[1–3]. In addition, dietary administration of various bioactive
phenol, chitosan, soybean isoflavones, lentinan, lipoteichoic acid, lac­
toferrin, and fucoidan have several positive effects such as immune
system enhancement, growth, survival and disease confrontation
against harmful microbes in aquatic organisms, natural bioactive
immunostimulant dietary additive technique is the new way to enhance
aquatic productions [4–8]. Microbial disease (bacteria, fungi, and vi­
ruses) outbreaks are considered the most imperative problem of aqua­
culture production, which can eventually lead to devastating financial
losses [11]. The modes of action of immunostimulants are boosting the

* Corresponding author. Department of Animal and Aquatic Sciences, Faculty of Agriculture, Chiang Mai University, Chiang Mai, Thailand.
** Corresponding author. Xiamen Key Laboratory for Feed QualityTesting and Safety Evaluation, Fisheries College, Jimei University, Xiamen, China.
E-mail addresses: jmusunyunzhang@163.com (Y.-Z. Sun), hien.d@cmu.ac.th (H. Van Doan).

https://doi.org/10.1016/j.fsi.2022.09.011
Received 6 June 2022; Received in revised form 3 September 2022; Accepted 5 September 2022
Available online 10 September 2022
1050-4648/© 2022 Elsevier Ltd. All rights reserved.
S. Vijayaram et al.
immune system of aquatic animals and also improving the immunity
level against harmful microbes, bioactive immunostimulants are already
been used to control pathogens in shrimp and fish including bacteria
(Aeromonas hydrophila, Aeromonas salmonicida, Vibrio anguillarum, Vibrio
vulnificus, Vibrio salmonicida, Streptococcus sp., Yersinia ruckeri) and vi­
ruses, which cause diseases such as hematopoietic necrosis, yellow head
virus, viral hemorrhagic septicemia and the parasite Ichthyophthirius mul­
tifiliis, these kinds of immunostimulants are supportive to boost survival
and reduced mortality rate in aquatic animals [9,10]. Aquaculture is a
vital and rapidly developing sector as it performs a very important re­
sponsibility to attain widespread protein foodstuff demands. The re­
sponsibility of aquaculture to expand the socio-economic implication of
some places is mainly obvious since it’s not only able to provide essential
nutrients but also a variety of employment opportunities are created
[12]. This review provides information about dietary administration,
functions, and doses of different bioactive immunostimulants to increase
healthy aquatic production and also enhance feed quality levels in the
aquaculture industry.
2. The roles of bioactive immunostimulants in aquaculture
2.1. Bioactive immunostimulants improve growth and digestive
Bioactive immunostimulants are present in plants, animals, and
microbes or can be synthetically produced; the natural derived bioactive
immunostimulants have various biological actions such as antioxidant,
antitumor, cytotoxic, an inducer of apoptosis and cell cycle arrest,
antimicrobial, larvicidal, chemotactic, antifouling, antimelanogenic,
and anti-inflammatory activities [13]. Bioactive immunostimulants can
be classified into two types such as macromolecules (carbohydrates,
proteins, nucleic acids, lipids, and polysaccharides) and micro molecules
(natural products, primary and secondary metabolites), both the bio­
molecules play a major role in aquaculture. Bioactive immunostimulants
are complex organic molecules, which are present in all living organ­
isms, while such bioactive immunostimulant substances maintain the
metabolic process of all living organisms [15]. Moreover, bioactive
immunostimulants are shaped in the body and maintain the structure
and growth, while they could be characterized as necessary for body
functions [16]. The bioactive immunostimulants contain numerous
positive responses such as the immune system strengthening, antioxi­
dant activity, mediation of hormones, and butyric acid production in the
colon as well as combination and/or dilution of structure in the gut, the
small intestine is not only the fatal position for nutrient digestion and
absorption but also strongly connected with a different region of intes­
tinal antigens and bacteria to control gut and whole-body health [14].
Similarly, Ashraf et al. (2020) defined bioactive immunostimulant
substances as the material that can cause stimulating effects on living
tissue [17].
2.2. Bioactive immunostimulants modulate gut microbiota
Dietary immunostimulants feed additives were described as of quite
chemical characteristic nature, containing nutritional and non-
nutritional possessions as well as bioactive immunostimulants, which
may connect with direct or indirect physiological responses of fish
species [18]. Moreover, dietary feed additives of carvacrol, and/or
thymol koi carp (Cyprinus carpio) [20] from (Allium sativum) garlic
rainbow trout (Oncorhynchus mykiss) [21] have revealed noteworthy
possessions on gut health, digestive enzyme activity, intestinal immu­
nity, and extra supportive photogenic targets for the progress of aquatic
feed, the dietary immunostimulant additive stimulates and modifies the
intestinal microbiota conferring health benefits of the host, but notably
down-regulated the relative manner of tumor necrosis factor α (TNF-α)
(P = 0.0002) and transforming enlargement factor β (TGF-β) and
remarkably decreased malonaldehyde (MDA) levels in fish species.
Heterogeneous groups of functional feed additives, such as essential oils
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Fish and Shellfish Immunology 130 (2022) 294–308
(derived from aromatic plants) are widely used to enhance animal
nutrition since these bioactive immunostimulants are applied in live­
stock nutrition as well as in animal feed. Essential oils are an important
bioactive immunostimulant group; as such molecules are potential
chemotherapeutic alternatives without side effects like immunostimu­
lant, antimicrobial, anti-stress, antioxidant, and growth-stimulating ef­
fects while there is no ecological or harmful side effects linkage.
Additionally, essential oils may exhibit a positive impact on the gut
health of livestock as well as fish species [22]. Additionally, the colo­
nization of gut microbiota has an important function in the regulation of
non-specific and specific pathways of the immune system [24]. The in­
testinal microbiota of fish has an extremely imperative responsibility
due to gastrointestinal growth, higher digestive enzyme action, mucosal
tolerance maintenance, immunoregulation, and infection treatment
enhancement [25–28]. Similarly, the gut microbial composition changes
in the host’s microbiota through the utilization of bioactive immunos­
timulants from various sources [23]. Different types of dietary func­
tional feed additives such as probiotics, prebiotics, phytogenics, and
immunostimulants are used to enhance healthy aquatic animals’ pro­
duction and also enhance the feed quality in aquaculture, the dietary
immunogen additive increased growth performance, feed utilization,
protein efficiency, and also decrease feed conversion ratio consequently,
dietary immunogen additive increased higher body protein content
[19].
2.3. Bioactive immunostimulants improve immunity
The nutritional additives of β-glucan, chitosan, or raffinose have
been used to improve the non-specific immune system of koi (Cyprinus
rubrofuscus) by amplifying various resistant criteria such as phagocytic
activity, respiratory burst activity, lysozyme action, WBC, and SOD ac­
tion, finally, the bioactive immunostimulants are supportive to get
better the immune system of aquatic animals [31]. MyD88 signaling
pathway is directly triggered by MAMPs of intestinal microbiota strains.
Different kinds of substances (lysozyme, protease, complements, lectins,
and immunoglobulins) are significant for skin mucosal immunity and
also for disease resistance in fish [29]. For example, the MyD88
signaling pathway plays a major part in the innate immune system
control, while on other hand some microbial components controlled the
adaptive immune system, increased digestive enzyme, protein content,
and reduced lipid content level, there are no differences in immune gene
expression those all the parameters confirmed by the control groups
(IgM and IgT) of rainbow trout (Oncorhynchus mykiss) head kidney [30].
Fishes treated with bioactive immunostimulants have generally
confirmed by phagocytic cell performance increase [32], as according to
literature the phagocytic cell action can be better by bioactive immu­
nostimulants due to the activation of a natural immune response, for
example, the inflammatory reaction before adaptive response such as
antibody production, excessive doses level of some immunostimulants
provoke immunosuppression in fish. The side effects of immunostimu­
lants have not been well-studied. The study concluded that immunos­
timulants are a vital role in to control of fish infections and the optimum
dietary immunostimulants are helpful to improve the growth of farming
fish culture [33]. Mendoza Rodriguez et al. (2017) examined that di­
etary additives of organic acids (polyhydroxy butyrate (PHB 2%), po­
tassium diformate (KDF 0.6%)), other biomolecules (carrageenan
(0.5%) and alginic acid (1%)) enhanced the immunological system of
red drum (S.ocellatus), as well as feed efficiency and weight gain, was
notably decreased in fish feed compared to the basal diet and together
bioactive immunostimulants [34]. Consequently, the bioactive immu­
nostimulant supplements have been shown to noticeably resilient
structure stimulation of fish [35]. In aquaculture, bioactive immunos­
timulants and their derivatives enhanced non-specific immune re­
sponses against various diseases, while these molecules have exhibited
effective immunostimulant properties in fish and shrimps [10].
S. Vijayaram et al.
2.4. Bioactive compoundsas immunostimulants in aquaculture
2.4.1. Plants derivedbioactive immunostimulants
Plant-based bioactive immunostimulants as supplements could show
the potential impact in aquatic organisms like enhanced gut health,
immune system, antimicrobial action and act as appetite stimulators, the
herbal bioactive immunostimulants only give positive effects; they
cannot be suggested owing to their remaining and other side effects in
aquatic animals [36]. Similarly, the active dietary supplementation of
herb and spices were capable to provoke and release intestinal enzymes,
mucosal serum immunities, and antioxidant response that will stimulate
the appetite; thus, rising food consumption and subsequently improving
the efficiency in Nile tilapia (Oreochromis niloticus), this dietary additive
has no significant changes in feed conversion ratio and also dietary in­
clusion was not affected to fish health [37]. In addition, various plants
derived bioactive elements such as flavonoids, alkaloids, phenolics,
terpenoids, tannins, steroids, glycosides, saponins, and essential oils
have been described to show positive effects namely immunostimula­
tion, growth promotion, anti-pathogenic, appetite stimulation, and
anti-stress in fish species, this study pointed out that dietary additives of
herbal bioactive immunostimulant as helpful to enhanced physiological
and hematological responses in fishes [36]. The plant-based bioactive
immunostimulants were commonly tonics for the release of digestive
enzymes and have a direct effect on intestinal microflora, while ac­
cording to literature these compounds can increase the digestibility, feed
conversion, and protein synthesis of the rainbow trout (Oncorhynchus
mykiss) [38]. Different types of plant bioactive immunostimulants have
been added to feed supplements, demonstrating significant impacts in
farmed animals, while such dietary additives are safe for animals, con­
sumers, and the environment [39]. Abha and Abhisweta (2020) reported
that the animal feed industry utilized plant bioactive immunostimulants
to develop animal nutrition and health [40]. Additionally, Baleta et al.
(2022) suggested that dietary additives of 1% ethanolic katuk extract
bioactive immunostimulant enhanced growth, appetite, and improved
food utilization in Orange-spotted grouper (Epinephelus coioides) [41].
2.5. Polyphenols
The polyphenols group is one of the major classifications of bioactive
immunostimulants produced by plants to defend against different
pathogenic bacteria, fungi, and viruses and also defend response to
various types of abiotic stress [42]. Therefore, polyphenols are sug­
gested as alternative options for the (partial) replacement of chemicals
and antibiotics in aquaculture development [43,44]. In addition, poly­
phenol dietary additive (tannins from 2.5 to 20.0 g/kg) was used for
immunological parameters enhancement in rohu (Labeo rohita) finger­
lings, while these supplements have shown numerous positive effects
such as resistance against oxidative stress improvement, reproductive
performance, growth performance and infection resistance in different
fish species such as European sea bass (Dicentrarchus labrax), black carp
(Mylopharyngodon piceus), Wuchang bream (Megalobrama amblyce­
phala), common carp (Cyprinus carpio), convict cichlid (Amatitlania
nigrofasciata) and beluga sturgeon (Huso huso) [10,45–51]. Dietary
polyphenol supplement (0.2%) was extracted from chestnut and olive
mill wastewater, this polyphenol additive improved the growth perfor­
mance, immunological parameters, and antioxidant status, and also feed
conversion ratio of fish-fed polyphenols notably diminished and differ­
entiated from the control groups in common carp (Cyprinus carpio) fin­
gerlings [52]. Dietary Clarius lazera phenol additives have been used in
various concentrations (35, 75, 150, and 300 mg/L) and enhanced he­
matological parameters and also elevated LDH, glucose, and cortisol,
and significantly reduced serum cholesterol concentration in catfish
(Siluriformes). The dietary polyphenol was supportive to improve the
fish’s immune system [53]. In addition, dietary tannins polyphenol
additive (0.1%) was derived from chestnut wood and were in various
analyzes such as growth parameters, growth gene expression, enzymatic
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Fish and Shellfish Immunology 130 (2022) 294–308
activity, and hematological and non-specific immune parameters in
beluga under experimental conditions. Finally, the optimum level of
0.1% dietary polyphenol was supportive to improve fish health [51].
2.6. Flavonoids
Flavonoids are the most important ingredients of plants [54]. Dietary
Allium mongolicum Regel flavonoids (AMRF) supplement (40 mg/kg)
enhanced the immune system, antioxidant status, regulation of gene
activation, and infection resistance of Cephalopholis argus (Peacock hind)
against Aeromonas hydrophila as well as considerably decreased in serum
cortisol, liver MDA content, serum ALT and AST activity [55]. Dietary
supplementation of R. verniciflua extract flavonoids enhanced feed
quality level and fish production, exhibiting also a significant impact on
antiviral effects in fish viral diseases like infectious hematopoietic necrosis
virus (IHNV) and viral hemorrhagic septicemia virus (VHSV) [56].
2.7. Alkaloids
Alkaloids are found in plant tissues as a type of water-soluble salts of
organic acids, esters, or sugars rather than as free bases [57]. Moreover,
alkaloids contain different types of protein bands, which have a signif­
icant role in immune system enhancement and infection resistance
against various pathogens in fish [58]. Subsequently, dietary additives
of Gelsemium elegans alkaloids (40 mg/kg) increased intestinal villus
length, villus number, muscle growth, antioxidant activity, intestinal
immune activity, cytokine-related genes expression, and also to
improved the disease resistance of Wuchang bream (Megalobrama
amblycephala), while firmicutes abundance was reduced at phylum level
after the alkaloid feeding [59]. Zhou et al. (2016) reported that dietary
additives (25 g/kg) of the fibrous root of Rhizoma Coptidis containing
alkaloids could enhance the immune system and disease resistance in
common carp (Cyprinus carpio) [60].
2.8. Fructooligosaccharides
FOS is derived from blue agave plants, vegetables, fruits, cereals, and
grains [61], composed of D-fructans, in which fructose is attached by
b-(2–1) glycosidic connections and associated with an end glucose unit.
Additionally, FOS may be linked via tolls like receptors (TLR2) pointing
to macrophages [62] and stimulating the expression of antimicrobial
peptides (Leap), which have a significant role in natural immune pro­
tection and disease resistance in fish (Megalobrama amblycephala) [63].
Likewise, dietary supplementation of FOS (1%,2%, and 3%) increased
lysozyme action, salinity stress resistance, leukocyte production, and
elevated digestive enzyme function in Caspian roach fry (Rutilus rutilus)
[64]. Similarly, our research group described that diet containing (5
g/kg) FOS improved intestinal enzyme activity, and lysozyme action,
and also decreased triglyceride (TG) levels compared to the control diet
in Japanese flounder (Paralichthys olivaceus) [59,65]. Dietary supple­
mentation of FOS (0.3 and 0.6%) has shown a beneficial effect on the
innate immune response of Nile tilapia (Oreochromis niloticus),
confirmed by the major progress of serum lysozyme action and IgM level
and also both plasma and phenoloxidase performance were noticeably
(P < 0.05) affected only by dietary FOS levels with the maximum
standards experiential in fish fed 0.6 and 0.3% FOS, respectively [66].
2.9. Galactooligosaccharides
Galactooligosaccharides (GOS) incorporate 2–20 different prebiotic
substances of galactose and glucose and are generally formed by the
enzymatic hydrolysis of lactose [67]. GOS has a small point of poly­
merization, which improves its metabolization rate by probiotics [68].
The use of GOS (1% and 2%) dietary supplement enhanced humoral and
mucosal immune response, survival rate, and increased salinity resis­
tance in Caspian roach (Rutilus rutilus) fry as well as there is no negative
S. Vijayaram et al.
impacts in the experimental condition [69]. Nutritional management of
GOS as an immunostimulant in rockfish (Sebastes schlegeli) presented
that feeding rockfish with (1%) of GOS for 8 weeks, notably improved
skin mucus as well as humoral immune criteria, and also this bioactive
immunostimulant not affected to the physiological and hematological
responses in fish species [70]. Yukgehnaish et al. (2020) reported that
the dietary supplement of GOS (10 g/kg− 1) acted as a significantly
important prebiotic for the Atlantic salmon (Salmo salar) and also this
bioactive immunostimulant affected protein concentration in the wet
body and protein retention were reduced by 6 and 9%, respectively,
relative to the basal fish [71], Caspian roach (Rutilus rutilus) [72],
rainbow trout (Oncorhynchus mykiss) [73], common carp (Cyprinus car­
pio) [25,74], Caspian white fish (Rutilusfrisii kutum) [75], narrow-clawed
crayfish (Astacusleptodactylus Leptodactylus) [76], and rockfish (Sebastes
schlegelii) [70].
2.10. Inulin
Inulin exists in several fruits, vegetables, and cereals, like leeks,
onions, chicory, bananas, wheat, garlic, and artichokes. It is reported
that dietary inulin supplement (5 g/kg) could improve hematocrit and
NBT activity levels and lysozyme activity as well as there is no negative
impact on physiological and hematological response in Nile tilapia
(Oreochromis niloticus) [77]. Gupta et al. (2020) stated that dietary inulin
additives can control the hematological and/or serum biochemical pa­
rameters (erythrocyte counts, mean corpuscular volume (MCV), he­
matocrit, mean corpuscular hemoglobin (MCH), hemoglobin, mean
corpuscular hemoglobin concentration (MCHC), leukocyte counts,
serum glucose or serum total protein levels, differential leukocyte counts
and serum cholesterol); thus this indicator has a prominent role in fish
health [78]. Furthermore, Mo et al. (2015) presented that dietary inulin
additive (2%) improved growth action and the natural immune system
of grass carp (Ctenopharyngodon Idella) [79]. Another study about inulin
supplement (15–20 g/kg) in Barramundi (L.calcarifer) juveniles; re­
ported significant effects in histology, biochemical parameters, and
immunohistology [80].
2.11. Salidroside
Salidroside is a glucoside of tyrosol, which is present in the plant
species of Rhodiola Rosea. It has been considered, along with rosavin, as
one of the most significant factors responsible for the known anti-
depressant and anxiolytic actions of this plant [81]. Zhang et al.
(2021) reported that salidroside was found not only in the plant Rhodiola
Rosea but also in a few Chinese herbs like Angelica root [82], Ganoderma
lucidum [83], Prunella vulgaris, etc., as well as this bioactive immunos­
timulant enhanced the immune system and antiviral effects challenging
against coxsackievirus B3 and dengue virus [84]. Xie et al. (2020) pointed
out that salidroside (0.1% and1.0%) components were highly present in
Prunella vulgaris extracts, and these factors enhanced non-specific im­
mune activity, respiratory burst activity, phagocytic activity reduced
mortality rate, and treat Olive flounder (Paralichthysolivaceus) challenge
with Uronema marinum. Finally [4], Yang et al. (2020) mentioned that
dietary additive of salidroside improved the immune system in crucian
carp (Carassius carassius) and enhanced the defense action against
harmful microbes, main at the concentration of 100 mg/kg for four
weeks. The protective effect of salidroside on crucian carp (Carassius
auratus) might be considered as an alternative to antibiotics for con­
trolling fish infections in aquaculture as well as the quantity of
A. hydrophila in the kidney and spleen was considerably decreased in
salidroside additive diet groups (P < 0.05).
2.12. Geniposide
Geniposide is a bioactive iridoid glycoside; it is present in different
types of medicinal herbs, namely Gardenia jasminoides (fruits).
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Fish and Shellfish Immunology 130 (2022) 294–308
Geniposide showed a variety of pharmacological responses both in vitro
and in vivo applications, such as antidiabetic, anti-inflammatory, neu­
roprotective, hepatoprotective, analgesic, antidepressant-like, car­
dioprotective, antioxidant, immune-regulatory, antithrombotic, and
antitumor activity. Geniposide is derived from Gardenia jasminoides Ellis,
a Chinese herbal medicine [85]. Nevertheless, few studies demonstrate
the efficacy of geniposide as an immunostimulant in fish species, dietary
administration of geniposide 400–800 mg/kg increased total collagen
and alkaline-insoluble collagen content in grass carp (Ctenopharyngodon
Idella) muscle than control and also fish fed diet containing geniposide
notably reduced muscle crude lipid content compared to control groups
[86]. Geniposide was shown as an efficient diet supplement to control
the apoptosis-related factor, reduce WSSV (white spot syndrome virus)
simulation and increase the survival rate of WSSV-challenged red
swamp crayfish (Procambarus clarkii) [87]. Similar beneficial effects of
lysozyme reaction were also observed in crucian carp (Carassius car­
assius) [88], and Nile tilapia (Oreochromis niloticus) [66] feeding
geniposide-containing food. According to the literature, the use of 100
mg geniposide/kg was proved positive effects on immune reaction
improvement and infection resistance in crucian carp (Carassius car­
assius), one of the most (freshwater) cultivated fish species in China.
Furthermore, this dietary supplement was tested for innate immune
response improvement, upregulated resistant connected gene exhibi­
tion, and infection resistance against Aeromonas hydrophila in crucian
carp (Carassius carassius) [89].
2.13. Lectins
Lectins are carbohydrate-binding proteins, present in most plants
and some animals [90]. Lectins are considered as a carbohydrate
detection domain, mainly binding sugars while there are different
classifications of animal lectins namely C-type, I-type, F-type, L-type,
P-type, M-type, R-type, F-box lectins, chitinase-like lectins, galectins,
intelectins, calnexin, and ficolins. Lectins play a major role in intracel­
lular and extracellular, extracellular lectins are vital for cell signaling
and pathogen recognition while intracellular lectins play a major part in
the convey of proteins movement throughout the cells and in protein
sorting [91]. C- type lectins, which are responsible for stimulating the
immune system, are particularly linked with PAMPs on the surfaces of
several harmful microbes, providing them the ability to detect a broad
diversity of pathogens [92]. Several classifications of lectins have been
recognized in rainbow trout serum through calcium ion chains to
A. salmonicida lipopolysaccharide [93]. On the other hand, opsonizing
lectins, which are present in fish serum, may be beneficial for fish health,
as are considered for the immune mechanism and prevention of aquatic
animal diseases. The components play an imperative function in pro­
tecting the host by identifying pathogens and then increasing their
elimination and appearance in phagocytic cells of the immune system.
The mammalian mannose-associated lectin can opsonize in different
types of organisms such as yeasts, bacteria, and surrounded viruses, like
HIV or influenza [94]. Similarly, the potential function of lectins as
non-recognized substances in all living organisms’ immunity [95].
Likewise, the crucial role of lectins in molecular biology and immuno­
logical analysis in animals [96], while the importance of lectins in the
innate immune reaction of mammals is well known [97]. In addition,
Liang et al. (2020) pointed out that lectins from immune cells of marine
invertebrates were effective in improving disease resistance against
V. vulnificus and V. pelagicus in aquatic animals and also reduced mor­
tality rate in aquatic animals [98].
2.14. Carotenoids
Carotenoids are natural pigments, with a significant role in all living
organisms like plants, algae, fungi, bacteria, and animals. Animals
cannot synthesize carotenoids, so they obtain them from their diet [99].
Shrimp-extracted carotenoid supplements of 100 and 200 mg/kg could
S. Vijayaram et al. Fish and Shellfish Immunology 130 (2022) 294–308

lead to immune system enhancement and infection resistance of Carp
against A. hydrophila [100]. The addition of carotenoids in feed
exhibited a beneficial role in both fish and fishery products as patho­
genic organisms’ inhibition was achieved. Carotenoids’ dietary addi­
tives range (50 and 100 mg/kg) varies from species to species [101].
Many researchers exhibited that a dietary additive of 100 mg car­
otenoids/kg can boost the immune system, survival, and growth as well
as avoid harmful effects of lipid peroxidation in different species such as
rainbow trout (Oncorhynchus mykiss), giant tiger prawn (Penaeus mon­
odon) and European bullhead (Cottus gobio) [102–104]. Natural immu­
nostimulants, namely dietary supplements of carotenoids boosted the
immune system, disease resistance, and antioxidant function of aquatic
animals and also downregulated in superoxide dismutase but high
catalase activity compared to the control one [105]. The function of
plants based bioactive compounds as immunostimulants in aquatic an­
imals has been summarised in Table 1.
2.15. Animal originated bioactive immunostimulants
2.15.1. Chitosan
Chitosan is a type of alkaline polysaccharide existing in the shell of
aquatic organisms namely crabs, shrimps, and shellfish. Chitosan is a
conventional non-toxic, safe, bio-compatible, and bio-degradable poly­
mer substance. The main effect of chitosan molecule progression is to
significantly increase the growth of aquatic species [106], reduce the
growth of harmful microbes [107], purify the aquaculture water [108],
and improve the resistance of aquatic organisms to infections [106].
Chitosan can chelate metal ions via the role of amino acid groups and
hydroxyl substances and might decrease the heavy metal ions in water;
thus chitosan is considered a major defender factor for the aquatic
species [109]. In addition, immunostimulants are responsible for the
improvement of inflammatory cell function namely polymorphonuclear
leucocytes, cytokine, and macrophages [110]. In aquaculture, dietary
chitosan improved the protective effect against bacterial infections and
enhanced the immune response in hybrid striped bass (Morone saxatilis)
[111], while recently, chitosan was presented as an effective immu­
nostimulant in different fish species [112]. Dietary supplement of chi­
tosan enhanced non-specific immune response under experimental
conditions of healthy control, and additionally, chitosan was tested
against the immune response modulation in rohu (Labeo rohita) [113].
Diets with chitosan for rainbow trout (Oncorhynchus mykiss) [114], olive
flounder (Paralichthys olivaceus) [115], koi (Cyprinus rubrofuscus) [116],
and kelp grouper (Epinephelus bruneus) [107] demonstrated that such a
bioactive immunostimulant could improve growth, natural immunity,
infection, stress resistance, enhance immunological criterion and in­
crease water quality. The mechanism of chitosan action as an immu­
nostimulant in fish has not been fully established yet. Similar studies
showed that chitosan additives might increase the innate immune sys­
tem response of various fish species [117]. Oushani et al. (2020) re­
ported the action of chitosan as an immunostimulant in rainbow trout
(Oncorhynchus mykiss), as they observed that a chitosan (2.5 g/kg) diet
was favorable on immunological criteria and increased the survival rate
of rainbow trout (O. mykiss) against environmental stress [114]. Wu
et al. (2020) reported that the immunostimulatory feature of chitosan
for olive flounder (Paralichthys olivaceus) activates the innate immune
system of fish species, thus this action exhibits a defense role in the fish
body through amino moieties [115].
2.16. Lactoferrin
Lactoferrin is a globular glycoprotein with a molecular mass of about
80 kDa that is widely represented in different secretory fluids namely
milk, saliva, tears, and nasal secretions. Lactoferrin is one of the sig­
nificant bioactive mechanisms of the immune system in the body; it has

Table 1
Plants originated bioactive compounds as immunostimulants in aquaculture.
Origin Bioactive Aquatic organisms Immune response References
immunostimulants

Plant Fructooligosaccharides Caspian roach ↑lysozyme function, improvement of IgM level, No significant different ACP and [63,65]
increases PO
Common carp
Nile tilapia
Japanese sea bass ↑growth, digestion and immune activities [190]
Tambaqui Promote growth and improved healthiness [191]
Juvenile grouper Epinephelus Improved immune system and intestinal morphology [192]
coioides
Galactooligosaccharides Caspian roach ↑ Humoral and mucosal immune reaction [69,71,72,
Rainbow trout 75]
Narrow-clawed
Crayfish
Common Carp Controlled innate immune response in skin mucosa [193]
Pacific white shrimp Modulate gut microbiota composition, reduce stress and enhanced immune system [194]
Inulin L. calcarifer ↑ hematocrit, NBT and lysozyme activity, biochemical parameters and immuno- [63,79]
Rainbow trout haematology
common carp ↑growth performance, innate immune response and antioxidant activity [195]
Nile tilapia Improved fish health under salinity stress condition [196]
Salidroside Crucian carp ↑ immune related gene and non specific immune system [4,105]
Paralichthysolivaceus
Geniposide Crucian carp ↑ innate immune response, upregulated immune gene expression, RPA [65,188]
Nile tilapia
Crayfish Anti inflammatory, antioxidant and antiviral activity [197]
Polyphenols Common carp fingerlings ↑haematological parameters(erythrocytes and haemoglobin), anti oxidant status [51]
Amatitlania nigrofasciata Improved humoral and mucosal response and antioxidant activity [198]
Lates Calcarifer Improved growth, mucosal immune response and liver oxidative status [199]
Flavonoids C.argus ↑immune system, antioxidant activity, regulation of immune gene expression [7,54]
Trachinotusovatus
Ctenopharyngodon idella ↑Antioxidant, anti inflammatory and immune response [200]
Alkaloids Megalobramaamblycephala ↑antioxidant activity, Intestinal immune activity, RPA [58,59]
common carp
Pacific white shrimp Improved growth response, survival rate, immune response and antibacterial [201]
activity

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S. Vijayaram et al. Fish and Shellfish Immunology 130 (2022) 294–308

antimicrobial activity (bacteriocide, fungicide) and is part of the innate osmotic pressure of the cytoplasm. Peptidoglycan was also involved in
defense, mainly against mucose. Lactoferrin connects with DNA and the binary division during bacterial cell reproduction [123]. Oral dietary
RNA, polysaccharides, and heparin, and performs the biological supplements of peptidoglycan (0.2 mg/kg) extracted from Bifidobacte­
response in complexes with these ligands [118]. The dietary additive of rium thermophilum could act against vibriosis and white spot syndrome in
100 mg/kg Lf enhanced the immune response, respiratory burst, leu­ kuruma shrimps (Marsupenaeus japonicas) as well as reduce mortality
kocytes peroxidase content, and phagocytic index in gilthead sea bream and increase the survival rate in shrimp [124]. Likewise, dietary addi­
(Sparus aurata) [119]. [120] Morshedi et al. (2020) observed that the tives of cellular components like cell wall (CW), peptidoglycan (PG), and
dietary supplement (1200 mg/kg) of Lf could enhance low salinity lipoteichoic acid (LTA) enhanced physiological and immunological
stress, tolerance of air exposure, natural immune response, and mucus response, while notably decreased feed conversion ratio (FCR) was
secretion of juvenile orange-spotted grouper (Epinephelus coioides), as noticed in all the treatments compared with the control group in
well as dietary LF, did not affect the growth rate of this species under the orange-spotted grouper (Epinephelus coioides) [125]. [126] Kondo et al.
condition applied in this study. Similarly [35], Luna-Castro et al. (2021) (2021) demonstrated that dietary additives of A3a-PG (8 g A3α-PG/kg)
represented that the nutritional additive of Lf at a level of 100 mg/kg led to the immune system enhancement, disease resistance, and growth
increased the innate immunity and infection resistance of sea bream performance of Japanese flounder (Paralichthys olivaceus) as well as the
(Pagrus major) and Asian catfish (Siluriformes), as well as this study, highest dose explored in the previous report, (16 g A3α-PG/kg), also
described that support the possible use of Lf as an immunostimulant for failed to show any significant influences, although no obvious pathology
farmed fish species. Several Lactoferrin (Lf) products have been classi­ was observed. Another case of dietary additive of peptidoglycan (0.18
fied and evaluated, but bovine lactoferrin (BLf) has received attention g/kg for5 days/week) exhibited an increase in the immune system and
for its potential for animal protection. Owing to its immunoregulatory infection resistance of black tiger shrimp (Penaeus monodon Fabricius)
function, BLf may stimulate antiviral, antifungal, and antibacterial and there is no significant changes to the growth [127]. The immunos­
functions and subsequently may activate efficient defense against timulatory effect of microbial peptidoglycan is acknowledged from the
different microbial infections in some fish species according to the dose laboratory verification process, which can stimulate innate immune
and administration methods [121]. Additionally, dietary Lf supple­ responses, phagocytic index, and survival rate and infection resistance
mentation of 100 mg/kg for 1 week the immune system improvement of against aquatic pathogens in aquatic animals [128].
diverse fish species such as goldfish (Carassius auratus), rainbow trout
(Oncorhynchus mykiss), Atlantic salmon (Salmo salar), red sea bream 2.18. Lipopolysaccharides
(Pagrus major) and Asian catfish (Siluriformes) [122]. The function of
animals-base bioactive compounds as immunostimulants in aquatic Lipopolysaccharides (LPS) are huge molecules incorporating a lipid
animals has been summarised in Table 2. and a polysaccharide controlled of O-antigen, outer core, and inner core
connected with a covalent bond, while they are attending in the outer
2.17. Bacterium originated bioactive immunostimulants layer membrane of the Gram-negative bacteria. LPS are the components
of the gram-negative bacteria cell wall and also turn on B cell prolifer­
2.17.1. Peptidoglycan ation. LPS injected into red sea bream (Pagrus major) exhibited improved
Peptidoglycan or murein is a polymer consisting of sugars and amino macrophage phagocytic action [129]. The LPS are very effective even in
acids that forms a mesh-like peptidoglycan layer outside the plasma extremely low doses; while they can be derived from bacteria by
membrane of most bacteria, forming the cell wall. The sugar component chemical extraction methods and present better immunostimulating
consists of alternating residues of β-(1, 4) linked N-acetyl glucosamine properties during their use in fish species [130]. Ali et al. (2021) sug­
(NAG) and N-acetylmuramic acid (NAM), and attached to the NAM is a gested that LPS (1250 μg) played a significant role in rainbow trout
peptide chain of three to five amino acids. Peptidoglycan performs the (Oncorhynchus mykiss) and carp fish (Cyprinus carpio) species, as they are
structural function, strengthens the bacterial cell wall, and prevents the good immunomodulators and beneficial response in the disease resis­
tance of fish species, the lipopolysaccharides improved phagocytic ac­
tivity, total serum Ig and get better mucus lysozyme compared to
Table 2
Animal originated bioactive compounds as immunostimulants in aquaculture. untreated fishes mortality level is increased [32,131]. Abd El-Kader
et al. (2021) recommended that dietary supplement of LPS (50 and 100
Origin Bioactive Aquatic Immune response References
immunostimulants organisms
μg of LPS/fish) was injected intraperitoneally and successfully activated
innate cellular and secondary immune response as well O-specific
Animal Chitosan Rainbow [105,
↑haematological
linkage for activating the adaptive immune system and disease resis­
trout parameters, RPA 112–114]
Olive tance against A. hydrophila [132]. In contrast, oral consumption did not
flounder alter any of the aforementioned criteria. Similarly [133], Holen et al.
Koi (2021) reported that dietary additive of lipopolysaccharides was derived
kelp from Salmonella Typhimurium. The lipopolysaccharide component
grouper
enhanced better immunostimulant, phagocytic activity, and disease
Lactoferrin Asian ↑non specific [34,117,
catfish immune response, 118] resistance against Escherichia coli and A. salmonicida disease in trout
Atlantic respiratory burst, (Oncorhynchus mykiss). In addition [134], Mohammadi et al. (2020)
salmon leukocytes reported that a nutritional LPS additive of 0.1 mL was derived from
peroxidase content
Aeromonas hydrophila enhanced disease resistance against A. hydrophila
and phagocytic
index, RPA in (Oreochromis niloticus) Nile tilapia as well as for disease prevention
gilthead during unfavorable environmental conditions.
sea bream
Carotenoids Carp ↑antioxidant [98, 2.19. Lipoteichoic acid
rainbow activity, RPA. 100–102]
trout immune system
giant tiger response, Disease Dietary supplementation of lipoteichoic acid (LTA) was derived from
prawn resistance probiotics and is used to regulate immune gene expression as well as in
European ligand binding connections. Since LTA can stimulate the immune
bullhead
response in fish, it might be favorable for the control of disease in Gram-
↑- Enhance or Increase or Improve. positive bacteria such as Streptococcus iniae and Streptococcus agalactiae

299
S. Vijayaram et al.
[135]. Similarly [136], Yang et al. (2019) observed that dietary addi­
tives of both peptidoglycan and LTA extracted from B. pumilus SE5 can
stimulate TLRs/MyD88 signal pathway and the condition of antibacte­
rial agents and thus form the gut microbiota in orange-spotted grouper
(E. coioides). Additionally, dietary additive of LTA extracted from pro­
biotic B. pumilus SE5 was utilized to uncontrolled three antibacterial
peptides genes (epinecidin-1, hepcidin-1, and β-defensin) and immune
gene expression (TLR2, NOD2, IL-8, IgM) in the head kidney of Grouper
(Epinephelus coioides) [137]. Earlier studies have revealed that LTA is the
main cell wall element of Gram-positive bacteria, can associate with the
TLR-2 receptor, and triggers a cascade of responses. L. Plantarum LTA
extensively improved the feature of TLR2 and V. anguillarum flagellin
particularly improved TLR5. It is differentiated that LTA, flagellin, and
LPS bacterial components are mainly stimulated by TLR2, TLR5, and
TLR9 receptor pathways [138,139]. [140] Gao et al. (2016) suggested
that dietary LTA enhanced the natural immune system of silver pomfret
(Pampus argenteus). Probiotic dietary additives of LTA can regulate the
activation of several inflammatory factors and provoke apoptosis to a
lower level, as might also be determined by the physiological charac­
terization of the bacterium. Dietary supplements of LTA an imperative
function in the host cell TLR and also enhanced immune response,
probiotic colonization, and decreased pathogenic load while sustaining
a strong and active strength among the host and its gut bacteria.
2.20. Levan
Levan is a naturally occurring fructan, the homopolymer of fructose.
The molecular weight and degree of branching of levan differ depending
on the production organism. Moreover, the molecular weights of bac­
terial levan are much higher than the plant levan due to the multiple
branching [141]. Levan is the component of natural polymeric chain
linkages, which are mainly present in the microbial extracellular prod­
ucts of Bacillus subtilis, Bacillus polymyxa, Zymomonas mobilis, Acetobacter
xylinum, and a few plant species [78]. Similarly, dietary additives (25
g/kg) of microbial levan exhibited beneficiary effects in aquatic animals
like improved non-specific immune response, disease resistance,
growth, survival, and enhanced tolerance to thermal stress, and also
levan additive diets notably reduced the count of total viable aerobic
bacteria and Vibrio spp. in the gut region of orange-spotted grouper
(Epinephelus coioides H.) [142]. Moreover, the dietary additive of mi­
crobial levan (1.25%) enhanced the immune response and thermal stress
tolerance effect of rohu (L. rohita) juveniles, this optimum dietary ad­
ditive can confer protection against thermal stress tolerance in fish
species [143].
2.21. Fungal originated bioactive immunostimulants
Higher fungi are considered important sources of natural products
and have also exhibited various biological properties like anti-microbial,
anti-oxidant, immunostimulation, hypoglycaemic activities, and anti-
cancer [144]. Numerous higher fungi (Pleurotus ostreatus, Lentinula
edodes, Grifola frondosa, Coriolus Versicolor, Ganoderma lucidum, and
Schizophyllum commune) have bioactive polysaccharides in their fruiting
bodies; mycelium and broth culture [145]. Consequently, poly­
saccharides can significantly improve the growth and natural immune
response of fish and shrimp species [146–148].
2.22. Lentinan
Lentinan is a biological active transformer, which is shown to be
effective in protecting the host from oxidative damage without obvious
adverse activity and also diet additives of lentinan were used to modify
the gastrointestinal microbiota, which would be useful to sustain the
epithelial barrier role and enhance intestinal immunity. Lentinan is a
type of β-glucans with safe and pharmacological properties as well as
immunomodulatory, anti-oxidant, anti-inflammatory, anti-microbial,
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Fish and Shellfish Immunology 130 (2022) 294–308
and metabolic regulatory functions [147,149]. The nutritional addi­
tive of lentinan (100 μg/ml) has notably increased the intestinal anti­
oxidant, and inflammatory capacity by enhancing the performance of
SOD, CAT, and GSH-Px, and suppressing lipid peroxidation and also
lentinan may be effective for the treatment of gut inflammation
including IBD in juvenile taimen (Hucho taimen) [148,149]. [150].
Galindo-Villegas et al. (2016) reported that lentinan can induce anti­
microbial activity and stimulate the immune system through in vitro
methods. Moreover, dietary additives of lentinan (100–1000 μg/ml)
increased the immune system and disease resistance in Common carp
(Cyprinus carpio) by in vitro methods [151].
2.23. Mannan oligosaccharides
Mannan oligosaccharides (MOS) are extracted from the cell wall of
yeasts and recently researchers indicated the beneficial properties of
MOS in fish and shrimp species [152]. The possible effect of MOS (0.6%)
in aquaculture content is determined by the mannose receptor (endo­
cytic receptor), while these receptors communicate with macrophages
and endothelial cells to be identified together with individual glyco­
proteins and microbial glycan ligands [153]. MOS (0.6%) presented a
related consequence on the function of lysozyme in Nile tilapia (Oreo­
chromis niloticus), Japanese flounder (Paralichthysolivaceus), Rainbow
trout (Oncorhynchus mykiss), and Channel catfish (Ictalurus punctatus),
while the dietary additives of MOS were not affected in fish growth and
immune system [154]. MOS as feed supplements (6 g/kg) in aquaculture
of fish and shellfish may demonstrate to be supportive to the host by
increasing innate immunity, although more studies described that it is
needed to infer the appropriate level of MOS addition to diverse fish
species and also MOS dietary supplement was significantly decreased
lipogenic enzymes response in liver and resulted in a lower lipid
vacuolization and more regular-shaped morphology of hepatocytes
approximately the sinusoidal spaces, which could be associated to better
energy and good feed utilization because of the improvement of feed
utilization and the decrease of feed intake found in the current experi­
ment [155]. The dietary additive of MOS (0.4%) notably activated he­
molytic and phagocytic reactions in rainbow trout (Oncorhynchus mykiss
Walbaum) [156], while an amount of 2 g MOS/kg for 60 days was used
to evaluate certain immune components and immuno-associated en­
zymes in red sea bream (Pagrus major) as well as the specific immu­
nostimulatory activity of MOS in the gastrointestinal tract of fish and
also the performance of lysozyme, bactericidal and peroxidase in serum
and mucus of fish fed MOS diets improved over the control [157].
Similarly, the dietary feed supplement of MOS (0.6%–1%) was experi­
enced to increase blood protein levels in rohu (Labeo rohita) and Nile
tilapia (Oreochromis niloticus), and also dietary additive of MOS at a
0.6% and 1% dietary level stimulates growth and survival in rohu (Labeo
rohita) and Nile tilapia (Oreochromis niloticus). In difference, elevated
addition levels of immunostimulants led to an immunosuppressive effect
in rohu (Labeo rohita) and Nile tilapia (Oreochromis niloticus) [158].
2.24. β-Glucans
Glucans are primarily present in the cell walls of bacteria, fungi,
algae, lichens, and yeasts they obtain a helical or spiral backbone suit­
able to specific intra-factor hydrogen bonding. These β-glucans (10 mg/
kg) have been commonly expressed to control the immune function as
well as blood neutrophils, oxidative radical production, and superoxide
anion production in stimulated macrophages of Litopenaeusvannamei
juveniles [159]. The main component of β glucans is high-quality
immunostimulating factors. The abundance and nature of side chains
strongly affect the capability of the glucans to interfere with binding to
external receptors on the particular cells influencing the reaction of the
glucans as an immunostimulant [160]. These changes may indicate the
way to a mortality rate reduction of fish species against various patho­
gens. Innovative β–glucan receptors namely Dectin-1 and Toll-like
S. Vijayaram et al. Fish and Shellfish Immunology 130 (2022) 294–308

receptors on leukocyte surfaces of vertebrates have provided various
insights into the functions of immune responses induced by β-glucans
[161]. Oral dietary administration of yeast-derived beta-glucans was
showed that numerous positive affects such as enhance phagocytosis,
lysozyme levels, respiratory burst activity, and resistance against bac­
terial pathogens in several cultured fish species. The function of glucans
have been extensively studied in aquatic animals and the findings
indicate that β -glucans improved growth and significantly reduced
mortality rate in certain species of aquatic animals [162,163]. β-glucans
have been mentioned for their valuable role in several fish species such
as red sea bream (Pagrus major) [164], Atlantic Salmon (Salmo salar L.) is
utilized to improve growth, survival, immune system, disease resistance
against aquatic pathogens and reduced mortality rate in aquatic animals
[165].
The function of microbial-based bioactive compounds as immunos­
timulants in aquatic animals has been summarised in Table 3.
2.25. Algal bioactive immunostimulants
2.25.1. Alginate
Alginate was derived from brown seaweed, and it is a polysaccharide
component controlled by β-1, 4-D-mannuronic acid (M), and C5-epimer
a-L-glucuronic acid (G). A dietary additive of sodium alginate was used
to increase the non-specific immune system and infection resistance in
Tilapia (Oreochromis niloticus) [125,166]. In addition, a nutritional ad­
ditive of sodium alginate (2 g/kg) enhanced the survival of grouper
E. coioides by increasing its phagocytic activity, respiratory bursts,
lysozyme activity, alternative complement activity, and SOD activity,
disease resistance against Streptococcus sp. and iridovirus infection in
grouper [167]. It has been reported that the nutritional additive of so­
dium alginate (2 g/kg) could improve phagocytic activity, respiratory
bursts, lysozyme activity, alternative complement activity, SOD activity,
and disease resistance against V. alginolyticus but decreased GPX activity
in Pacific white shrimp (L. vannamei) [168].
2.26. Alginic acid
Alginic acid (or algin) is a naturally occurring, edible polysaccharide,
present in brown algae. Such compound is hydrophilic and forms a
viscous gum when hydrated. Accompanied by different metals such as
calcium and sodium, forms salts, which are recognized as alginates. Its
color ranges from white to yellowish-brown. Concerning its beneficial
results through consumption; previous studies demonstrated that alginic
acid could be used to enhance the nonspecific immune response in fish
species [125]. Dietary supplements of alginic acid (1 g/kg) improved
immune response, growth performance, and infection resistance against
WSSV disease in P. monodon, suitable dietary level of alginic acid is
protecting immune system response against WSSV infection in juvenile
P. monodon [169]. Similarly, ergosan is an algal derivative with alginic
acid (2 g/kg), which could be used to improve innate immune response
and infection resistance in different types of fish species [170]. Addi­
tionally, ergosan containing (0.5% and 1%) alginic acid derived from
Laminaria digitata, could enhance the immune response, phagocytic ac­
tivity, respiratory activity, and expression of interleukins and less
response in a humoral immune parameter in rainbow trout (Onco­
rhynchus mykiss) [171]. The dietary additive of ergosan (5 g/kg)
enhanced growth performance, protease, esterase activities, alkaline
phosphatase, lysozyme actions, and disease resistance against Yersinia
ruckeri in rainbow trout (Oncorhynchus mykiss) (110 g) [172].
2.27. Fucoidan
Fucoidan is a complex long-chain sulfated polysaccharide, present in
different species of brown algae. Commercially available fucoidan is
usually derived from the different seaweed species namely Fucus ves­
iculosus, Cladosiphon okamuranus, Laminaria japonica, and Undaria pin­
natifida. Fucoidan (3% and 6%) promotes several biological effects like
immunostimulation, disease resistance improvement, growth, and sur­
vival, whereas serum Albumin/Globulin (A/G) ratio and blood glucose
level exhibited decreasing trend in diverse fishes and shrimps [173].
Saeed et al. (2021) reported that dietary fucoidan (200 mg/kg of body
weight, group 12–15 g) boosted phagocytic activity and disease resis­
tance of shrimps as well as overdoses of several immunostimulants to
induce immunosuppression in fish [174]. The side effects of immunos­
timulants have not been well-studied. Dietary supplements of fucoidan
(1 g/kg) increased the immune system (circulating hemocytes, PO ac­
tivity, RBs, phagocytic activity) and disease resistance against
V. alginolyticus in shrimps. The study reports concluded that dietary
fucoidan’s most important role is to enhance the immune system of
shrimp species [175]. Finally, oral administration of fucoidan (15 g/kg)
derived from Sargassum polycystum could reduce the infection of White
Spot Syndrome Virus (WSSV) and reduce mortality rate, increase survival
level in black tiger shrimp P. monodon [176].

Table 3
Microbial bioactive compoundsas immunostimulants in aquaculture.
Origin Bioactive Aquatic organisms Immune response References
immunostimulants

Microbes (Bacteria and Peptidoglycan kuruma shrimps ↑immune system response, RPA, antibacterial and antiviral effects [122,124,
fungi) Japanese flounder 125]
Penaeus monodon
sea cucumber Potential immunomodulatory factor [202]
Regulation of innate immune response
spotted sea bass [203]
Lipopolysaccharides Red sea bream ↑phagocytic activity and disease resistance against antibacterial activity [127,131]
trout
Channa argus Induced antioxidant and immune response [204]
Exopolysaccharides Zebrafish ↑immune system response, antibacterial effects, higher expression of TLR1 [189]
and TLR 2
Pacific white Good immune modulator and preventive factor against vibriosis [205]
shrimps
Zebrafish Modification changes of gut microbiota but not affected SCFAs [206]
Lipoteichoic Acid Silver pomfret ↑TLR, RPA [137]
Levan Labeo rohita ↑Lys, TP, A: G, RBA, RPA [140]
common carp Potent nutraceutical and immuno additive agents [207]
Cyprinus carpio Growth promoter and antibacterial agents [208]
Lentinan juvenile taimen ↑TGF-β, TNF-α, IL-1β, IL-6 and IL-8, ↑SOD, CAT, and GSH-Px, RPA [148,149]
Senegalese sole Modulate immune system and regulate gut microbiota [209]

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301
S. Vijayaram et al.
2.28. Laminarin
Laminarin is the most significant component derived from plants and
seaweeds; Laminarin has a lot of bio-functional performances such as
antitumor, anti-apoptotic, anti-inflammatory, anticoagulant, and anti­
oxidant activity. The biological activities of laminarin can be improved
after appropriate chemical modifications, sulphation, and novel pro­
cessing techniques. Studies on feeding laminarin-rich extracts to animals
point out its suitability as an efficient component for food applications
[177,178]. Laminarin is generally low molecular weight (e.g., 5 kDa)
and their inter-chain linkages with glucans residues are of great
importance [179]. [180] Cui et al. (2021) demonstrated that laminarin
injection can change the expression of Arginine kinase (AK), and anti­
oxidant activity, and reduced the activity of Staphylococcus aureus, Lis­
teria monocytogenes, Escherichia coli, and Salmonella typhimurium.
Similarly [181], Shanmugavel and Krishnamoorthy (2021) reported that
laminarin may act as an immunostimulant and the energy source of
crustaceans [179]. Meng et al. (2020) demonstrated that dietary lami­
narin of 1 g/kg enhanced growth activity, feed efficiency, and the
nonspecific immune reaction of E. coioides and also The levels of
Creatinine (CREA) and UREA, as well as the action of alkaline phos­
phatase (ALP), were lower than of the control. There was no major
difference in the levels of alanine aminotransferase (ALT) and, aspartate
aminotransferase (AST) between control groups and treated groups. This
study recommended that laminarin regulates the immune response and
induces growth of the fish.
2.29. Ulvans
Ulvans are derived from the cell wall of green seaweeds; they contain
sulfated polysaccharides, Ulva was elevated in dietary fiber which
stimulates gastrointestinal health and is linked to a reduction in the
incidence of chronic diseases as well as biological activities of dietary
ulvans contains several positive responses such as immunomodulating,
antiviral, antioxidant, antihyperlipidemic and anticancer activity in
human and animals (including fish) [181,183]. In literature, it was re­
ported for the first time that dietary supplementation (1 g/kg) of ulvans
component could enhance immune system response and disease resis­
tance against bacterial and parasitic infection and there was no signifi­
cant difference in growth performance among fish for any of the diets
tested of Nile tilapia (Oreochromis niloticus) [184]. [185] Ponce et al.
(2020) suggested that U.ohnoi containing ulvans element was nontoxic
and potential application as a vaccine adjuvant and/or nutraceuticals in
aquaculture. Ulvans (0.5 mg/fish) was used to enhance immune gene
Table 4
Various bioactive compounds as immunostimulants in aquaculture.
Origin Bioactive immunostimulants Aquatic organisms
Algae Alginic acid Penaeus monodonRainbow trout
Yeast β-Glucans Litopenaeusvannamei
Red sea bream
Atlantic Salmon
Mannanoligosaccharides Rainbow trout
Nile tilapia
Seaweed Alginate Tilapia
GrouperE. Coioides
Fucoidan P. monodon
Laminarin E. coioides
Ulvans P. monodon
L. vannamei
Nile tilapia
↑- Enhance or Increase or Improve.
Abbreviations of immunological parameters: ACP- Acid phosphatase; RPA-reduce pathogenic activity; IgM-ImmunoglobulinM; TLC-Total leukocyte count, THC-
Total haemocyte count; SOD-Superoxide dismutase; GSH-Px, Glutathione-peroxidase; CAT-Catalase; TAC - Total antioxidant capacity; Lys- Lysozyme activity; PA-
Phagocytic activity; PI- Phagocytic activity PoA-phenoloxidase activity; TP-Total protein; A:G, Albumin/Globulin; RBA- Respiratory burst activity; SOD- Super
oxide dismutase; RBC- Red blood cell; WBC - White blood cell; IL-1a; Interleukin 1a; TNF-a, Tumor Necrosis Factor a; TAS-Total antioxidant status; ACP- the alternative
complement pathway; PO activities-total peroxidase enzyme concentration; ACPA-the alternative complement pathway activity.
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Fish and Shellfish Immunology 130 (2022) 294–308
expression and regulate immune pathways in flatfish (Senegalese sole)
juveniles. Dietary supplements of ulvans as sulfated polysaccharide el­
ements contain numerous health-beneficial effects such as anticoagu­
lant, antiviral, antioxidative, anticancer, and immunomodulating
activities. In addition, dietary additives of ulvans help improve aquatic
animal health and there is no negative impact on aquatic animals [186].
Dietary supplementation range of ulvans (0.05%) improved immuno­
logical parameters (respiratory burst, total hemocyte count, and phe­
noloxidase activities) of shrimps and also survival and challenging tests
in giant tiger prawn (P. monodon) and Pacific white shrimp
(L. vannamei), The dietary administration of ulvan was an effective
immunostimulant for L. vannamei and P. monodon [187]. The function of
other original bioactive compounds as immunostimulants in aquatic
animals has been summarised in Table 4.
3. Conclusion
This review is based on the last few years’ literature data analysis and
provides an enlightening direction for bioactive immunostimulant
improvement in the aquaculture industry. As a comprehensive study
was needed to improve bioactive immunostimulants, this review
concluded that bioactive immunostimulants sources, types, functions,
and administration methods are beneficial for the improvement of
healthy aquatic production and also for the increase of feed quality
levels. Due to this review report, information was presented about
bioactive immunostimulants, which are beneficial with a decreased
negative impact on aquatic animal health. Thus, such a report mainly
focused on positive responses analysis. The utilization of plant, animal,
bacterial, fungal, and algal-originated bioactive immunostimulants is
strongly recommended for improved aquatic animal health and aquatic
environment enhancement. Biomolecules’ functional feed additives
improve healthy aquatic productions and enhanced aquatic feed quality
levels and are also less toxic, cost-effective, and environmentally
friendly. The next steps of our research group will focus on the extrac­
tion, characterization, and identification of biomolecules from different
natural sources, biomolecules interaction analysis from the body, iden­
tification of novel bioactive immunostimulants, able to improve func­
tional nutritional supplements in the modern aquaculture industry. This
study information is enlightening to the future research direction of
novel bioactive immunostimulants in the aquaculture industry.
Declaration of competing interest
Authors have no conflict of interest to declare for the publication of
Immune response References
↑ immune system, growth and antiviral activity [169,172]
↑phagocytic activity, RPA, resistance against bacterial pathogens [164,165]
↑TLC [154,156]
↑ blood protein, RPA
PA, PoA, RBA [166,167]
↑ immune system, RPA [176]
↑ non specific immunity, RPA [179]
THC, RBA, PoA [184,187]
↑immune response, RPA
S. Vijayaram et al.
the present work.
Data availability
Data will be made available on request.
Acknowledgments
We wish to acknowledge the national natural science foundation of
China (Grant no. 32072990), Xiamen Marine and Fisheries Development
Fund (Grant No. 19CZP018HJ04), Industry-University Cooperation
Project of Fujian Province (Grant No. 2018N5011) for supporting this
research work. This research work was partially supported by Chiang
Mai University, Chiang Mai, Thailand.
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